Pembrolizumab plus docetaxel for patients with metastatic castration-resistant prostate cancer (mCRPC): Randomized, double-blind, phase 3 KEYNOTE-921 study.
Authors: Daniel P. Petrylak, Raffaele Ratta, Nobuaki Matsubara, Ernesto Pablo Korbenfeld, Rustem Gafanov, Loic Mourey, Tilman Todenhöfer, Howard Gurney, Gero Kramer, Andre M. Bergman, Pawel Zalewski, Maria De Santis, Andrew J. Armstrong, Winald R. Gerritsen, Russell Kent Pachynski, Seok-Soo Byun, Xin Tong Li, Charles Schloss, Christian Heinrich Poehlein, Karim Fizazi
Journal: Journal of Clinical Oncology (2023)

19 Background: Docetaxel is a treatment option following disease progression on a next-generation hormonal agent (NHA) for patients with mCRPC, but there is an urgent need for more efficacious treatments. The randomized, double-blind, phase 3 KEYNOTE-921 study (NCT03834506) evaluated the efficacy and safety of pembrolizumab + docetaxel vs placebo + docetaxel for participants (pts) with mCRPC who had received prior NHA therapy. Methods: Eligible pts were ≥18 years old, had mCRPC that progressed on androgen deprivation therapy, had received 1 prior NHA, and had an ECOG performance status of 0 or 1. Pts were randomized 1:1 to receive 200 mg pembrolizumab Q3W or placebo for ≤35 cycles (~2 years) in combination with 75 mg/m 2 docetaxel Q3W for ≤10 cycles and 5 mg prednisone BID. The dual primary endpoints were radiographic progression-free survival (rPFS; tested at first interim analysis) per PCWG-modified RECIST 1.1 by blinded independent central review and overall survival (OS; tested at final analysis). The key secondary endpoint was time to initiation of the first subsequent anticancer therapy (TFST; at first interim analysis). Safety was one of the secondary endpoints. Results: Between May 30, 2019 and June 17, 2021, 1030 pts were randomized to receive pembrolizumab + docetaxel (n=515) or placebo + docetaxel (n=515). The median (range) time from randomization to data cutoff date of June 20, 2022 at final analysis was 22.7 mo (12.1−36.7). Baseline characteristics were generally balanced between arms; approximately half of pts in each arm had received prior abiraterone. Pts in the pembrolizumab + docetaxel arm received a median (range) of 12 (1–35) cycles of pembrolizumab and 9 (1–12) cycles of docetaxel; pts in the placebo + docetaxel arm received a median (range) of 12 (1–35) cycles of placebo and 9 (1–10) cycles of docetaxel. The dual primary endpoints of rPFS (median 8.6 mo with pembrolizumab + docetaxel vs 8.3 mo with placebo + docetaxel; HR 0.85, 95% CI 0.71−1.01; P=0.0335) and OS (median 19.6 mo vs 19.0 mo; HR 0.92, 95% CI 0.78−1.09; P=0.1677) were not met. Median TFST was 10.7 mo vs 10.4 mo, respectively (HR 0.86, 95% CI 0.74−1.01). Treatment-related AEs occurred in 94.6% (grade ≥3 in 43.2%) and 94.9% (grade ≥3 in 36.6%) of pts with pembrolizumab + docetaxel vs placebo + docetaxel. 2 treatment-related deaths with pembrolizumab + docetaxel and 7 with placebo + docetaxel were reported. Immune-mediated AEs and infusion reactions occurred in 23.3% (grade ≥3 in 6.2%) and 12.3% (grade ≥3 in 1.2%) of pts with pembrolizumab + docetaxel vs placebo + docetaxel, most commonly pneumonitis (7.0% vs 3.1%) and hypothyroidism (6.4% vs 3.3%). Conclusions: The addition of pembrolizumab to docetaxel did not significantly improve rPFS or OS for pts with mCRPC and did not result in a notable increase in treatment-related AEs. Clinical trial information: NCT03834506 .